Volume 23, No 12, Dec 2013

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 23 Issue 12, December 2013: 1396-1413

ORIGINAL ARTICLES

The mINO80 chromatin remodeling complex is required for efficient telomere replication and maintenance of genome stability

Jin-Na Min¹, Yanyan Tian², Yang Xiao³, Ling Wu³, Lei Li² and Sandy Chang¹

¹Department of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, CT 06520, USA
²Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA
³Department of Genetics, MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence: Sandy Chang(schang@yale.edu)

The INO80 (inositol requiring mutant 80) chromatin remodeling complex plays important roles in transcriptional regulation and DNA replication and repair, and consists of several functional protein subunits, including the critical Ino80 ATPase catalytic subunit. While the function of INO80 has been studied in yeast and mammalian cell lines, we do not know how mIno80 contributes to the maintenance of genome stability to prevent cancer development in mice. Here, we use a conditional knockout approach to explore the cellular and organismal functions of mIno80. Deletion of mIno80 results in profound cellular proliferative defects and activation of p21-dependent cellular senescence. While mIno80 is required for efficient repair of DNA double strand breaks, its depletion did not impact upon the formation of γ-H2AX and 53BP1 DNA damage foci, or the activation of the ATM-CHK2-dependent DNA damage response. mIno80 deletion inhibited the generation of single-strand DNA, resulting in defects in homology-directed DNA repair (HDR) at telomeres. Fragile telomeres were prominent in mIno80Δ/Δ MEFs, suggesting that chromatin remodeling is required for efficient telomere replication. mIno80−/− mouse embryos die early during embryogenesis, while conditional deletion of mIno80 in adult mice results in weight loss and premature death. In a p53−/− tumor-prone background, mIno80 haploinsufficiency favored the development of sarcomas. Our studies suggest that the mIno80 chromatin remodeling complex plays important roles in telomere replication, HDR-mediated repair of dysfunctional telomeres, and maintenance of genome stability.

10.1038/cr.2013.113

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